Traumatic brain injury (TBI) is a major public health problem. Every year, about 2.5 million U.S. citizens sustain TBI, resulting in over 50,000 deaths, 235,000 hospitalizations, and over 117,000 disabilities. Despite the great morbidity and mortality, there are no pharmacological treatment options for TBI, which can be attributed to two major factors, including: 1) the lack of approaches for efficiently overcoming the blood-brain barrier (BBB) for drug delivery to the traumatized brain, and 2) the lack of therapeutic agents that are effective on TBI. The broad goal of this project is to combine the most recent advances in emerging nanotechnology and TBI biology to develop a novel regimen for TBI treatment. As preliminary work, we have synthesized novel nanoparticles, called autocatalytic traumatized brain-targeted nanoparticles (ATBT NPs), and demonstrated that they could efficiently mediate drug delivery to the traumatized brain. We have also identified macrophage migration inhibitory factor 20 (MIF20), a first-in-class small molecule MIF agonist that we recently designed and synthesized, as a promising agent for TBI treatment, although the in vivo use of MIF20 as a free agent has been suffered from its low solubility and systemic toxicity. Based on this progress, we propose a new strategy for TBI treatment: intravenous delivery of MIF20-loaded ATBT NPs. We will test the strategy through optimization and characterization of ATBT NPs for systemic drug delivery the traumatized brain in Aim 1 and evaluation of the therapeutic benefit of MIF20-loaded ATBT NPs in Aim 2. Successful completion of the proposed study will establish a new platform for systemic drug delivery to the traumatized brain as well as a new paradigm for TBI treatment, which can be translated into clinical applications for improving the quality of life and survival of TBI patients.